- MRL/lpr mice develop a systemic autoimmune disease which is characterized by peripheral lymphadenopathy and a spectrum of autoantibodies that strongly resemble human SLE. Genes, both the MRL genetic background and the single gene lpr which is a mutant fas gene, play major roles in the development of this autoimmune syndrome. MRL/+/+ mice develop many of the same autoantibodies and clinical disease as MRL/lpr mice; however, the disease does not develop until much later in life. MRL/+/+ mice also do not have the lymphoproliferation which is characteristic of the lpr mice due to the homozygous fas defect. When the LPR gene is bred onto other genetic backgrounds, however, the manifestations of autoimmunity are substantially different and even the degree of lymphoproliferation varies. Most notable, none of the clinical syndromes of glomerulonephritis or arthritis occur in the other congenic lpr mice. Anti-Sm, anti-dsDNA, anti-Su, and anti-P antibodies are often not found in the other lpr strains, although they are found in the MRL/+ mice. Certain autoantibodies, however, are more prominent in the congenic lpr mice; for example, C57BL/6-lpr mice produce higher levels of IgM rheumatoid factor with specificity for IgG2b than do MRL/lpr mice. The objective of the current application is to extend the understanding of the mechanisms or failure of immunoregulation in MRL/lpr mice. The main emphasis will be on the role of T cells and B cells. A new initiative in this renewal is to investigate the role of Fc-gamma receptors in systemic autoimmunity. In more clinically directed studies, potential therapies for SLE will be developed by developing a mouse model of autologous stem cell reconstitution. The following aims are proposed: 1. What is the role of Fc-gamma receptors in the autoimmune and lymphoproliferative syndrome of MRL/lpr mice? 2. Does the intrinsic expression of the MRL background genes in T cells help determine the specificity of the autoimmune manifestations induced by the lpr mutation? 3. Is the pace of MRL/lpr disease dictated by events that occur after the early lymphocyte stage of ontogeny? 4. Does the genotype of the B cell control the lymphoproliferation of T cells?